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IGF-II Serum Levels Are Normal in Children with Silver-Russell Syndrome Who Frequently Carry Epimutations at the IGF2 Locus

University Children’s Hospital, 72076 Tübingen, Germany; and Institute of Human Genetics, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, 52074 Aachen, Germany

Address all correspondence and requests for reprints to: PD Dr. Gerhard Binder, Pediatric Endocrinology Section, University-Children’s Hospital, Hoppe-Seyler-Strasse1, 72076 Tübingen, Germany. E-mail: gerhard.binder{at}med.uni-tuebingen.de.

Context: Epigenetic mutations of 11p15 encompassing IGF2 are present in short children with Silver-Russell syndrome (SRS) with high frequency (31–50%). It has been speculated that these mutations characterized by demethylation of ICR1 cause diminished IGF2 expression.

Objective: We aimed to determine the prevalence of pathologically low IGF-II serum levels in children with SRS.

Subjects: SRS was defined by birth weight or length below the 3rd percentile, lack of postnatal catch-up growth, and the presence of two of the following characteristics: typical face, relative macrocephaly, and skeletal asymmetry. Serum samples of 30 patients were available. Mean age was 5.4 ± 2.1 yr.

Methods: The serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-2, and IGFBP-3 were measured by RIA and compared with age-related reference values and with serum concentrations measured in age- and gender-matched controls born small for gestational age (SGA), but lacking major dysmorphic features. Analysis of genomic DNA was possible in a subgroup of children with SRS: the methylation status of the ICR1 locus on 11p15 and the parental origin of chromosome 7 were analyzed in 9 and 23 children, respectively.

Results: Demethylation of ICR1 was found in 44% and uniparental disomy in 17% of the tested children with SRS. The median IGF-II serum level in SRS was 441 µg/liter (range, 238–875). This was significantly higher than in the SGA controls: 387 µg/liter (range, 265–596) (P < 0.03), but below the median value of the age-related reference, which was 532 µg/liter. The four children with SRS and ICR1 demethylation had high-normal and normal IGF-II serum levels that were higher than the levels of their SGA controls. IGF-I, IGFBP-2, and IGFBP-3 serum levels were not different between the SRS children and their SGA controls.

Conclusions: Our data render it unlikely that demethylation of ICR1 on 11p15 does cause diminished IGF-II serum levels in children with SRS. This observation does not exclude deficient IGF-II action before birth.

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